Tumor gene therapy by systemic delivery of plasmid DNA with cell-penetrating peptides

Künnapuu, Kadri; Veiman, Kadi-Liis; Porosk, Ly; Rammul, Evelin; Kiisholts, Kristina; Langel, Ülo; Kurrikoff, Kaido

doi:10.1096/fba.1026

Cited by 27 publications

(16 citation statements)

References 46 publications

(48 reference statements)

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“…Since the enzyme cannot pass through the cell membrane, we could achieve this goal by using the advantages of CPPs in covalent conjugation with the TAL enzyme. Because of their ability to cross the cell membrane, CPPs are used in the delivery of various therapeutic agents, including DNA, siRNA, and proteins into the cells 34 . Therefore, in the current study, a TAT‐RsTAL fusion protein was generated, and its potential for decreasing the tyrosine content in the intracellular compartment, and consequently, the inhibition of melanogenesis in B16F10 cells was examined.…”

Section: Discussionmentioning

confidence: 99%

“…33 Hence, TAL can be a promising treatment for L-Tyr-related disorders. Since the enzyme cannot pass through the cell membrane, we could achieve this goal by using the advantages of CPPs in cova- 34 Therefore, in the current study, a TAT-RsTAL fusion protein was generated, and its potential for decreasing the tyrosine content in the intracellular compartment, and consequently, the inhibition of melanogenesis in B16F10 cells was examined. Molecular modeling showed that the fused CPP is exposed and does not interfere with the tetramerization domain or active site of the protein.…”

Section: Further In Silico Evaluation Of Tat-rstal Constructmentioning

confidence: 99%

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Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia‐lyase and a TAT‐penetrating peptide

Behzadipour

Sadeghian

Bahraman

et al. 2020

Biotechnology Progress

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Hyperpigmentation disorders negatively influence an individual's quality of life and may cause emotional distress. Over the years, various melanogenesis inhibitors (mainly tyrosinase inhibitors) have been developed, most of which with low efficacy or high toxicity. Although metabolic engineering by deviation in the flux of substrate is of considerable interest, trials to develop a melanogenesis inhibitor based on L-tyrosine (L-Tyr) restriction are missing. We propose a novel proteinaceous melanogenesis inhibitor called tyrosine ammonia-lyase (TAL), an enzyme that catalyzes the conversion of L-Tyr to p-coumaric acid and ammonia. Since the cell membrane can act as a barrier for intracellular protein delivery, we have covalently conjugated a recombinant TAL enzyme from Rhodobacter sphaeroides (RsTAL) to a trans-activator of transcription (TAT) cell-penetrating peptide (CPP) to afford the intracellular delivery. The heterologously expressed TAT-RsTAL fusion protein was delivered successfully into B16F10 melanocytes as confirmed by the direct fluorescence microscopy with increased intensity from 30 to 180 min. TAT-RsTAL showed sufficient intracellular activity of about 0.83 ± 0.04 and 0.34 ± 0.03 nmol•mg −1 •s −1 for the native and inclusion body-extracted conjugates, respectively. The conjugate inhibited melanin biosynthesis in B16F10 cells in a time-dependent manner. Melanin accumulation was inhibited by 12.7 ± 6.2%, 28.2 ± 5.7%, and 33.9 ± 2.9% compared to the nontreated control groups after 24, 48, and 72 hr of incubation, respectively. L-Tyr restriction had no significant effect on the cell viability up to a concentration of 100 μgml −1 even after 72 hr. According to the observed hypopigmentary effect of the conjugate in this study, TAT-RsTAL can be suggested as a melanogenesis inhibitor for further investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Further In Silico Evaluation Of Tat-rstal Constructmentioning

confidence: 99%

Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia‐lyase and a TAT‐penetrating peptide

Behzadipour

Sadeghian

Bahraman

et al. 2020

Biotechnology Progress

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“…However, their relevance beyond sensitive reporter models and utility in medicine has been demonstrated only in limited cases. As an example of this, we have previously demonstrated cancer delivery by adding targeting components to the delivery vector 3,15 . In the current work however, we utilized the native biodistribution bias of the carrier itself.…”

Section: Discussionmentioning

confidence: 99%

Effective lung-targeted RNAi in mice with peptide-based delivery of nucleic acid

Kurrikoff

Freimann

Veiman

et al. 2019

Sci Rep

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We have previously developed efficient peptide-based nucleic acid delivery vectors PF14 and NF55, where we have shown that these vectors preferentially transfect lung tissue upon systemic administration with the nucleic acid. In the current work, we have explored the utilization and potential of these vectors for the lung-targeted gene therapy. Accordingly, we assessed the efficacy of these peptides in (i) two different lung disease models – acute lung inflammation and asthma in mice and (ii) using two different nucleic acid cargos – siRNA and pDNA encoding shRNA. Using RNAi against cytokine TNFα, we showed efficient anti-inflammatory effects in both disease models and observed decreased disease symptoms. Our results highlight the potential of our transfection vectors for lung gene therapy.

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“…The activation occurs through proteolytic cleavage by MMP in the tumor tissue, liberating the CPP component [18]. This strategy -termed aCPP (activatable CPP) -has been used for the tumor-targeted delivery of nucleic acid by using gene therapy [19] or delivery of chemotherapeutics [20].…”

Section: Cancer Environment Responsive Strategiesmentioning

confidence: 99%

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Kurrikoff

Vunk

Langel

2020

Expert Opinion on Biological Therapy

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Introduction: In this review, recent developments and applications with cell-penetrating peptides (CPP) are discussed. CPPs are widely used tools for the delivery of various macromolecular therapeutics, such as proteins and nucleic acids. Areas covered: The current review focuses on recent important advances and reports that demonstrate high clinical and translational potential. Most important clinical developments have occurred with the CPP-drug conjugate approaches that target various protein-protein interactions, and these have been highlighted subsequently. Most of the applications are targeting cancer, but recently, noteworthy advances have taken place in the field of antisense oligonucleotides and muscular dystrophies, lung targeting, and trans-BBB targeting. Expert opinion: Successful applications and clinical development with the drug conjugate approaches are discussed. On the other hand, the reasons of why the nanoparticle approaches are not as far in development are analyzed.

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Tumor gene therapy by systemic delivery of plasmid DNA with cell-penetrating peptides

Cited by 27 publications

References 46 publications

Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia‐lyase and a TAT‐penetrating peptide

Introducing a delivery system for melanogenesis inhibition in melanoma B16F10 cells mediated by the conjugation of tyrosine ammonia‐lyase and a TAT‐penetrating peptide

Effective lung-targeted RNAi in mice with peptide-based delivery of nucleic acid

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

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